The present invention relates to a mass spectrometer that is capable of measuring a wide (ion) mass range in a single measuring process without repeating it, while achieving high sensitivity, high mass accuracy, and MSn analysis.
There has been a need for mass spectrometers that are capable of providing high sensitivity, high mass accuracy, MSn analysis, etc. in proteome analysis, etc. An example of how these analyses are conventionally carried out will be described.
A quadrupole ion trap mass spectrometer is a high-sensitivity mass spectrometer that is capable of MSn analysis. The basic principle of the operation of the quadrupole ion trap mass spectrometer is described in U.S. Pat. No. 2,939,952. A quadrupole ion trap is made up of a ring electrode and a pair of endcap electrodes. A radio frequency voltage of approximately 1 MHz is applied to the ring electrode, so that ions whose mass is higher than a predetermined value assume a stable state and can be accumulated within the ion trap. MSn analysis in an ion trap is described in U.S. Pat. No. 4,736,101 (Re. 34,000). In the system described in U.S. Pat. No. 4,736,101 (Re. 34,000), ions generated by an ionization source are accumulated within an ion trap, and precursor ions of desired mass are isolated (from the accumulated ions). After the isolation, a supplementary AC voltage, which resonates with the precursor ions, is applied between the end cap electrodes. This extends the ion orbit and thereby causes the precursor ions to collide with a neutral gas that has been filled in the ion trap, thereby dissociating the ions. The fragment ions obtained as a result of the dissociation of the precursor ions are detected. The fragment ions provide a spectrum pattern specific to the molecular structure of the precursor ions, making it possible to obtain more detailed structural information on the sample molecules. With this system, however, a mass accuracy of only 100 ppm can be obtained due to occurrence of a chemical mass shift that is attributed to collision with gas at the time of ion detection, a space charge that is attributed to the electrical charges, etc. Therefore, this system cannot be applied to fields in which high mass accuracy is required.
An attempt to achieve both high mass accuracy and MSn analysis is described in S. M. Michael et al., Rev.Sci.Instrum., 1992, Vol.63(10), p.4277–4284. This system can repeat ion isolation or dissociation within the ion trap to accomplish MSn. Ions ejected from the ion trap are accelerated coaxially into TOF. This arrangement makes it possible to accomplish higher mass accuracy than an ion trap. With this system, however, a mass accuracy of only 50 ppm can be obtained due to the divergence caused from collisions which occur during ion ejection from the ion trap. Therefore, this system cannot be applied to fields in which high mass accuracy is required.
A method of achieving both high mass accuracy and MSn analysis is described in Japanese Laid-Open Patent Publication No. 2001-297730. This system can repeat ion isolation or dissociation within the ion trap to accomplish MSn. Ions ejected from the ion trap are accelerated in an orthogonal direction in synchronization with their introduction into the acceleration region of the TOF region. This orthogonal arrangement of the ion introduction and ion acceleration directions makes it possible to accomplish high mass accuracy.
However, a new problem is created with this orthogonal ion trap/TOF. The arrival times of the ions reaching the acceleration region after they are ejected from the trap region are different depending on their mass. Suppose that the ions are accelerated at a certain timing (they are accelerated when middle-mass ions have just reached the acceleration region). In such a case, high-mass ions which have not yet reached the acceleration region and low-mass ions which have already passed the acceleration region are not detected. This puts a limit on the ion mass number range which can be accelerated and detected. As a typical example, the ratio of the maximum mass number to the minimum mass number, which can be detected at one time (this ratio is referred to as a mass window), is approximately 2. For example, to cover a mass range of 100 to 10000 amu with the mass window set to 2, it is necessary to divide the mass range into seven or more portions and measure them in parallel. This leads to a reduction in the number of times the measurement can be performed, thereby decreasing the sensitivity.
An attempt to solve the problem resulting from the occurrence of a mass window in the above-described orthogonal TOF is reported in The International Journal of Mass Spectrometry, vol. 213, pp. 45–62, 2002. In the system described in this publication, when ejecting ions, the potential difference between the endcap electrodes is increased while applying the ring voltage. At that time, since the ions are sequentially ejected in the order of decreasing mass, a wide mass range of ions can be introduced into the acceleration region of the TOF at nearly the same time. However, this system is disadvantageous in that the spread in the kinetic energy of low-mass (that is, high q value) ions is as large as nearly 1 kV, thereby considerably reducing the transmission at subsequent stages.
Another attempt to solve the problem resulting from the occurrence of a mass window is reported by C. Marinach (Universite Pierre et Marie Curie), Proceedings of the 49th ASMS Conference, 2001. To solve the above-described problem, this system increases the time taken for ions to travel from the ion trap to the TOF region so as to turn the ion beam into a pseudo-continuous current, as well as increasing the TOF repetition frequency to approximately 10 kHz, in order to measure a wide mass range of ions. However, this system is disadvantageous in that it is necessary to transfer ions a long distance between the ion trap and the TOF acceleration region with low energy, resulting in reduced ion transmission, reduced sensitivity, etc.
On the other hand, a method of achieving high mass accuracy is described in Proceedings of the 43nd Annual Conference on Mass Spectrometry and Allied Topics, 1995, pp. 126. This method sets the ion introduction direction from the ionization source to the TOF analyzer and the acceleration direction of the TOF region such that they are orthogonal to each other, thereby accomplishing high mass accuracy over a wide mass range. Furthermore, an intermediate pressure chamber under a pressure of 10 Pa is provided between the ionization source and the TOF region, and multipole rods (multipole electrode) are disposed therein to carry out collision damping, thereby enhancing the transmission between the ionization source and the TOF region. This system, however, cannot perform MS/MS analysis.
One method of achieving both high mass accuracy and MS/MS analysis is to use the Q-TOF (quadrupole/time-of-flight) mass spectrometer described in Rapid Communications in Mass Spectrometry, Vol. 10, pp. 889, 1996. In this method, ions subjected to mass selection in the quadrupole mass spectrometry region are accelerated and introduced into a collision cell. The introduced ions collide with gas within the collision cell and are thereby dissociated. The collision cell is filled with the gas at a pressure of 10 Pa and has multi-pole rods (multi-pole electrode) disposed therein. The dissociated ions gather toward the center axis direction, due to the action of the multi-pole electric field and the collision with the gas, and they are introduced into the TOF region, making it possible to accomplish MS/MS analysis. However, this system cannot perform MSn analysis (n≧3). Furthermore, since a plurality of types of dissociation occur after the ions are introduced into the collision cell, it may be difficult to estimate the original ion structure from ions generated as a result of the dissociation.